P1056: NEXT GENERATION SEQUENCING IDENTIFIES SUBGROUPS OF PATIENTS WITH TRIPLE NEGATIVE/ PRIMARY THROMBOCYTOSIS WITH DIFFERENT CLINICAL OUTCOMES
Authors: Valentina Sangiorgio, Rocco Giovanni Piazza, Federica Mottadelli, Fabio Pagni, Inzoli Elena, Carlo Gambacorti-Passerini, Gianni Cazzaniga, Elena Maria Elli
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: The majority of patients (pts) with essential thrombocythemia (ET) show somatic mutations of JAK2 (V617F or exon 12), CALR or MPL genes. However, in a proportion of cases there is no evidence of such mutations [so called “triple negative” essential thrombocythemia (TP-ET)]. Additionally, some pts with bona fide “primary thrombocytosis” (PT) (i.e., thrombocytosis not related to myeloid malignancies) do not fulfil the histologic criteria of ET as established by the WHO Classification. In pts with TP-ET or PT, Next Generation Sequencing (NGS) provide evidence of clonality in a proportion of cases. Moreover, it can identify subsets of pts with different clinical behaviors. Aims: We analyzed the clinical, laboratory and histologic findings in a cohort of pts with TN-ET or PT and correlated them with the molecular findings. We used the Sophia Genetics™ Myeloid Solution, a captured based NGS system used to identify somatic variants in 30 genes associated with myeloid malignancies. Methods: We conducted a retro-prospective analysis of adult pts with a history of persistent (>6 months) thrombocytosis [platelet count (PLT), ≥450x109/L] followed at the Hematology Unit of the San Gerardo Hospital in Monza, Italy. Inclusion criteria were the absence of diagnostic criteria for Philadelphia positive and negative myeloproliferative neoplasms with driver JAK2, CALR and MPL mutations. Secondary causes of thrombocytosis were excluded by the mean of clinical and laboratory analyses. Bone marrow trephine biopsy (BMT) were reviewed by two hematopathologists for confirmation. All pts enrolled had NGS analyses done at diagnosis or during follow up. Cases were classified as “NGS negative” (NGS-neg) if no myeloid mutations were identified or “NGS positive” (NGS-pos) if ≥1 mutation was detected. Only pathogenic mutations were considered in the final analysis. Results: 40 pts were included in the study. Median age at diagnosis was 48 years (range: 18-82). The female to male ratio was 2.3. Mean PLT was 553x109/L (range: 450-1838). The main clinical and laboratory findings are shown in Table 1. BMT was done in 33 pts (82.5%). Histologic features were consistent with ET in 63.3% of cases, whilst 36.4% of pts featured a normal bone marrow. 8 pts (20%) presented with an arterial thrombotic event within 1 year from diagnosis. 37 pts (94.5%) received an anti-PLT therapy. A cytoreductive therapy was administered in 22 pts (55%). After a median follow up of 10.6 years (range: 2.6-22.2), we reported thrombotic events in 7 (17.5%) pts. Interestingly all occurred in pts receiving both an anti-PLT therapy and a cytoreductive therapy. NGS was available in 38 pts: 21 (55.3%) were NGS-pos, 17 (44.7%) NGS-neg. Considering mutations with any variant allele frequency (VAF), NGS-pos pts showed an increased evidence of thrombotic events at diagnosis (28.6%) compared to NGS-negative pts (11.8%). This difference persisted even when considering only mutation with a VAF ≥5% (n=9). Similarly, the rate of thrombotic events occurring during follow up was different between NGS-pos (28.6%) and NGS-neg (5.9%) pts. Lastly, 7 pts (18%) presented with PLT ≥1000x109/L. All had a low IPSET score and, in spite of the severe thrombocytosis, none developed thrombotic and/or hemorrhagic events at presentation or during follow up. In this subset, NGS was negative in the majority (66.7%) of the cases. Summary/Conclusion: In TN-ET or PT, NGS seems to stratify pts with different clinical behavior (especially in terms of thrombotic risk) and thus provides useful clinical information Table 1Keywords: Thrombosis, Somatic mutation, Essential Thrombocytemia, Thrombocytosis